1. Technical Field
The present invention relates to methods of treating tissue of the human body, specially, methods of promoting cell proliferation and ingrowth around an implantable medical device.
2. Background Information
Various medical conditions, including vascular disease, frequently require surgical intervention to repair tissue damage and facilitate healing. Such surgical repairs can include repairs with known medical devices. In most cases, these medical devices need to be inert to both body's immune system and its coagulation system: the implanted device will have to mimic the body to such a degree that it actually becomes invisible to the body's defense mechanisms. Medical devices, including artificial vascular grafts, stent grafts, and heart-valve sewing cuffs are examples of devices that remain in the body permanently and thus must be hemocompatible throughout their service life. However, the conventional practice of having highly polished implantable medical device surfaces results in the poor cell proliferation and ingrowth around the implanted medical device.
To ensure that the device is hemocompatible following implantation of the device, proliferation and ingrowth of endothelial and other existing cells located in or in the blood vessel wall or in the blood stream is important to the successful treatment of the given medical conditions.
Methods that utilize immobilizing agents, such as extracellular matrix (ECM) proteins and peptides, directly onto the device surface were previously suggested to promote the integration and adhesion of the native cells onto the implanted device. This technique has been shown to be effective in small-diameter (<6 mm) vascular grafts, for which it is desirable that a layer of endothelial cells cover the entire inner surface of the device to prevent occlusion (Clapper D L et al (Clapper D L, Hagen K M, Hupfer N M, et al., “Covalently Immobilized ECM Proteins Improve Patency and Endothelialization of 4-mm Grafts Implanted in Dogs,” Trans Soc Biomat, 16:42, 1993, and Tweeden K S, Blevitt J, Harasaki H, et al., “RGD Modification of Cardiovascular Prosthetic Materials,” in Proceedings of the Cardiovascular Science and Technology Conference, Arlington, Va., Association for the Advancement of Medical Instrumentation, p 124, December 1993). Although, some studies have demonstrated, for example, that an appropriate combination of covalently immobilized ECM proteins can improve both the patency and endothelialization of small diameter vascular grafts, with the mechanism of endothelialization most likely being via promotion of pannus ingrowth, these studies were limited to small diameter vascular grafts.
Also, blood-compatible biomimetic coatings were suggested to encourage the growth of a layer of endothelial cells over the device surface so that the blood is no longer exposed to the foreign material. However, device makers have been reluctant to adopt the coatings, due in part to the cost and complexity the coatings can add to the regulatory approval process. For example, U.S. Pat. Pub. 2005/0187608 A1 teaches that implantable intraluminal medical devices, such as stents, may be affixed with vascular endothelial growth factor, VEGF, which acts selectively on endothelial cells. Other factors that promote the stimulation of endothelial cells suggested as coatings for medical devices included members of the fibroblast growth factor family. Various agents that accelerate cellular migration, including agents that upregulate integrins, were also suggested to increase endothelialization. Nitric oxide and pro-angiogenic agent were also suggested to promote endothelialization
Alternately, medical devices having, for example, nano-textured surfaces fabricated from a material, which by its physical material characteristics promotes the migration of endothelial towards the device were also suggested in the past.
We here provide an alternative reliable, simple and cost effective method of promoting cell proliferation and ingrowth around the implanted medical devices. The medical device implanted according to this method will be hemocompatible by becoming surrounded by the native tissue due to enhanced proliferation and ingrowth of the cells around the device, and especially at the anchoring location(s) of the device.